Download radiographic contrast media used in ERCP

GUIDELINE
ASGE Technology Status Evaluation Report: radiographic
contrast media used in ERCP
To promote the appropriate use of new or emerging
endoscopic technologies and those technologies that impact on endoscopic practice, the American Society for
Gastrointestinal Endoscopy Technology Assessment Committee has developed a series of status evaluation papers.
This process presents relevant information about these
technologies to practicing physicians for the education
and the care of their patients. In many cases, data from
randomized controlled trials are lacking and only preliminary clinical studies are available. Practitioners should continue to monitor the medical literature for subsequent
data about the efficacy, the safety, and the socioeconomic
aspects of these technologies.
BACKGROUND
Water-soluble iodine-based contrast media (CM) is injected into the biliary and the pancreatic ducts during
the performance of endoscopic retrograde cholangiopancreatography (ERCP).1 Most of our knowledge regarding
the efficacy, the safety, and the side effects of various
CM, however, derive from their intravenous use in radiology and only, to a lesser degree, from their use in ERCP.
This report reviews the use of CM in ERCP, including its relation to image quality, the likelihood for systemic absorption, and the risk for, and means of, reducing adverse
reactions. There are no evidence-based standards of practice for prophylaxis against contrast reactions during the
performance of ERCP. Current clinical practices are commonly based on radiologic recommendations for intravenous administration of CM.
monomer, and nonionic dimer. All are benzoic acid derivatives with molecular weights less than 2000. They possess one or two benzene rings and, therefore, are
monomers or dimers. They are hydrophilic, with low lipid
solubility and a low binding affinity for proteins. They
move freely in the extracellular space. The number of
particles into which they dissociate in solution determines the osmolality of these media. The number of
iodine atoms in the parent molecule determines the density of the CM and, therefore, the degree of attenuation of
x-ray photons.
Ionic monomers dissociate in solution into cations
(e.g., sodium or methylglucamine) and anions (the
iodine-containing benzene-ring component, such as
iothalamate or diatrizoate). These compounds are highly
osmolar (w1500 mOsm/kg for 300 mg iodine/mL) and
are termed high osmolality contrast media (HOCM). Nonionic CM does not dissociate and has the lowest osmolality
(w600 mOsm/kg for 300 mg iodine/mL) and is termed low
osmolality contrast media (LOCM). Ionic dimers dissociate
into two particles but carry 6 iodine atoms, so that the
osmolality remains low for the degree of x-ray attenuation
achieved.
EFFICACY AND EASE OF USE
Copyright ª 2005 by the American Society for Gastrointestinal Endoscopy
0016-5107/$30.00
doi:10.1016/j.gie.2005.07.006
The effect of CM on image quality during ERCP is the
resultant interaction of density, viscosity, and osmolality.
Although no optimal iodine concentration has been defined for ERCP, the most commonly used CMs provide between 150 and 300 mg iodine/mL. Such concentrations are
derived from vascular and urographic experience where,
in general, equivalent iodine concentrations produce
equivalent images for the same radiographic conditions.
Dilution of HOCM directly affects radiographic quality.
The image quality appears to be similar when comparing
HOCM and LOCM.2 However, HOCM has become the
standard agent used for ERCP, primarily on the basis of
its low cost, approximately 20 to 40 times less than that
of LOCM.1
The quality of fluoroscopy and the technique of injection also influence the quality of images obtained. Ease
of injection, especially through small-diameter catheters,
480 GASTROINTESTINAL ENDOSCOPY Volume 62, No. 4 : 2005
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TECHNICAL CONSIDERATIONS
All CMs currently available can be classified into one
of 4 groups: ionic monomer, ionic dimer, nonionic
ASGE Technology Status Evaluation Report: radiographic contrast media used in ERCP
is greatly affected by CM viscosity. Clinical experience suggests that small gallstones within large ducts may be better
imaged with dilute contrast, whereas strictures and pancreatic-duct anatomy are better imaged with full-strength
contrast. The need for increased volumes and the introduction of air during syringe changes are potential disadvantages of diluting contrast.
The osmolality and the ionic nature of the CM are believed to be the major factors responsible for many of
the adverse events that occur after intravascular administration. It has been postulated that low osmolar agents
may be safer than high osmolar agents for the performance of ERCP, because reduced osmotic fluid shifts
across ductal mucosa and pancreatic acini may yield less
prominent increases in intraductal pressures. However,
this has not been confirmed in clinical studies of postprocedure pancreatitis or other local complications.
Delayed reactions are defined as occurring between 1
hour and 7 days after the contrast injection and usually
are mild. While it may be difficult to verify the association
of delayed adverse events to CM use, they are assumed to
occur in 2% to 8% of patients who receive intravenous
CM.6 The prevalence of intravenous CM reactions is lower
with LOCM than with HOCM.7 Fatal reactions are exceedingly rare with both types of CM (1:170,000), and there is
no difference in associated mortality between the two
types.6,8
The data specific to ERCP-related CM reactions are very
limited, prompting us to review the literature for intravenous CM. It is important to acknowledge that neither skin
testing nor test challenge doses have been predictive for
significant reactions related to intravenous exposure. Patients at increased risk for adverse reactions include those
with a history of allergic diathesis, e.g., asthma, and those
with a prior reaction to CM. Use of intravenous LOCM in
such patients would decrease the risk of reactions compared with HOCM.
SYSTEMIC ABSORPTION
PROPHYLAXIS AGAINST SYSTEMIC REACTIONS
The risk for serious adverse reactions largely relates to
the amount of contrast that is systemically absorbed,
which, in turn, depends on the volume and the pressure
of injection, the duct studied (greater during pancreatography), and the iodine concentration of the contrast
agent. The rise in serum iodine concentration associated
with instillation of CM during ERCP is about 1/100 that
seen with intravenous administration.3 Diagnostic ERCP
yields 0.6% of the systemic iodine load that results from
coronary angiograms.4 Thyroid function has been used
as an indirect marker of systemically delivered iodine,
and no clinical thyroid abnormalities have been identified
in these studies.4,5
Systemic adverse reactions to CM used in ERCP have
been documented, but their true incidence is unknown.
Adverse reactions can be characterized as idiosyncratic
or nonidiosyncratic, based on their proposed mechanisms. In general, nonidiosyncratic reactions are most
likely dose and osmolality related, whereas idiosyncratic
(anaphylactoid) reactions usually occur immediately.
Acute CM reactions can be subdivided into minor, intermediate/moderate, and severe (Table 1).6 Minor reactions
are self-limiting, are usually of short duration, and, in general, do not require specific therapy; intermediate or
moderate reactions, in most cases, respond well to supportive treatment; and severe reactions, while very rare,
may require immediate resuscitative efforts. For this reason, it is important that appropriate emergency medications and resuscitative equipment are readily available.
There is no evidence-based standard of practice for
prophylaxis against contrast reactions during the performance of ERCP. Current clinical practices are commonly
based on radiologic recommendations for intravenous administration of CM. A single, small survey of 42 physicians
noted that 8% had personal experience with a suspected
CM reaction at ERCP, and 83% used prophylaxis in patients
with a prior reaction to CM or food allergies, e.g.,
shellfish.9
Prophylaxis with corticosteroids helps decrease the risk
of reactions to intravascular administration of CM but does
not eliminate it completely. Clinical experience has demonstrated that corticosteroids should be administered a
significant time before the procedure; a single dose within
2 hours of the procedure is inadequate to provide a protective benefit.10 All grades of systemic reactions occur
less frequently with LOCM than with HOCM; the combination of steroid pretreatment plus intravenous LOCM
yielded a lower rate of adverse reactions than placebo
plus LOCM.11 Most authorities combine corticosteroid
pretreatment and LOCM in patients with a history of
a moderate or severe anaphylactoid reaction to intravenous CM.10,12
Several premedication regimens have been proposed
by the American College of Radiology to reduce the frequency and/or the severity of reactions to intravenous
CM. Neither of these approaches has been tested in the
setting of ERCP, thus, their use cannot be recommended
as being evidence based. Two frequently used regimens13
are the following:
1. Prednisone, 50 mg by mouth at 13 hours, 7 hours, and
1 hour before CM, plus 50 mg diphenhydramine
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Volume 62, No. 4 : 2005 GASTROINTESTINAL ENDOSCOPY 481
SAFETY AND CLINICAL DATA
SYSTEMIC REACTIONS
ASGE Technology Status Evaluation Report: radiographic contrast media used in ERCP
TABLE 1. Categories of acute reactions*
Mild
Nausea, vomiting
Altered taste
Sweats
Cough
Itching
Rash, hives
Warmth
Pallor
Nasal stuffiness
Headache
Flushing
Swelling: eyes, face
Dizziness
Chills
Anxiety
Shaking
Treatment: Requires observation to confirm resolution and/or lack of progression but
usually no treatment; patient reassurance usually is helpful.
Moderate
Moderate degree of clinically evident focal or systemic signs or symptoms including:
Tachycardia/bradycardia
Hypotension
Bronchospasm, wheezing
Hypertension
Dyspnea
Laryngeal edema
Pronounced cutaneous reaction
Treatment: Clinical findings should be considered as indications for immediate treatment;
these situations require close, careful observation for possible progression to a
life-threatening event.
Severe
Life-threatening with more severe signs or symptoms, including:
Laryngeal edema
Profound hypotension
Unresponsiveness
Convulsions
Clinically manifest arrhythmias Cardiopulmonary arrest
Treatment: Requires prompt recognition and treatment; almost always requires
hospitalization.
*Data from the American College of Radiology Committee on Drugs and Contrast Media.13
(Benadryl; Pfizer, New York, NY) intravenously, intramuscularly, or by mouth 1 hour before the CM
injection.
2. Methylprednisolone, 32 mg by mouth 12 hours
and 2 hours before contrast medium injection. An antihistamine, as in regime 1, also can be added to this
regimen.
Alternatives to contrast-based ductography during performance of therapeutic ERCP in patients at very high risk
of serious CM reactions include the use of radiographic
imaging with ‘‘air contrastography’’14 and the use of cholangioscopy or pancreatoscopy without fluoroscopy.15
CM could provoke pancreatitis18; yet, no clinical risk has
been identified specifically based upon media type. A recent meta-analysis revealed no statistical difference in
the risk of clinical post-ERCP pancreatitis with the use of
HOCM vs. LOCM19; however, high osmolar contrast was
associated with an increased incidence of asymptomatic
elevations of pancreatic enzymes. The analysis included
a single crossover study and 5 randomized controlled trials in favor of LOCM, and 11 others that showed no benefit of one CM over another.19
ANTIBIOTICS IN CONTRAST MEDIA
A variety of risk factors for post-ERCP pancreatitis have
been identified.16,17 In theory, the intraductal presence of
The addition of nonabsorbed aminoglycoside antibiotics to CM has been advocated by some centers to decrease
septic complications of ERCP.20 There are few studies that
examine this question, and none have demonstrated a significant clinical advantage, although most have been small
and thus subject to a type II error.21-23
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RISK ASSOCIATED WITH POST-ERCP
PANCREATITIS
ASGE Technology Status Evaluation Report: radiographic contrast media used in ERCP
TABLE 2. Characteristics of radiographic contrast media*
Classification and
contrast media
Ionic monomer (HOCM)
Diatrizoate [Renografin]
[RenoCal] [Hypaque]
[Urografin] Iothalamate
[Conray] Metrizoate
Ioxithalamate Iodamide
Ioglicate
Ionic dimer (LOCM)
Ioxaglate [Hexabrix]
Nonionic monomer (LOCM)
Iopamidol [Isovue]
Iohexol [Omnipaque]
Ioversol [Optiray]
Iopromide [Ultravist]
Ioxilan [Oxilan] Iopentol
Nonionic dimer (LOCM)
Iotrolan [Iotrol]
Iodixanol [Visipaque]
Osmolality
mOsm/kg H2O
1400-2300
600
400-800
290
Cost per 50 mL
$3-$7
$37
$35-$50
$45-$55
HOCM, High osmolality contrast media; LOCM, low osmolality contrast media.
*Data from Kimmey et al1 and the American College of Radiology Committee on Drugs and Contrast Media.13
FINANCIAL CONSIDERATIONS
The costs of CM used during performance of ERCP vary
widely. Typically, 50-mL bottles of HOCM cost $3 to $7, compared with $35 to $55 for LOCM, (Table 2). These costs may
be separately billable to private insurers predicated on individual contract arrangements. Medicare includes the cost
of contrast in the global facility (ambulatory payment classification) reimbursement schedule for hospital or endoscopy center outpatient procedures and in the Diagnosis
Related Group payments for inpatient procedures.
RECOMMENDATIONS
The safety data derived from studies of the intravascular use of LOCM cannot be translated to ERCP in view of
their low incidence of serious adverse events with nonvascular use. The evidence is lacking to support LOCM as
a method for decreasing ERCP complications.
There is no justification for the routine use of LOCM
during ERCP. In patients considered at high risk for CMrelated reactions (i.e., those with a prior serious
anaphylactoid reaction to intravascular CM), premedication and/or substitution of LOCM may be considered as
an option based on the above-mentioned theoretical
considerations.
The low frequency of sepsis after adequate biliary and
pancreatic drainage at ERCP and the lack of data argue
against the practice of routinely adding antibiotics to
CM. Additional data are needed regarding the use of
antibiotics in contrast media for those disease states in
which optimal drainage cannot be accomplished.
REFERENCES
1. Kimmey MB, Al-Kawas FH, Carr-Locke DL, et al. Technology assessment status evaluation. Radiographic contrast media used in ERCP.
Gastrointest Endosc 1996;43:647-51.
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2. Martin DF, England RE, Rosch T, et al. Diagnostic quality in endoscopic
retrograde cholangiopancreatography: comparison between lodixanol and lopromide. Endoscopy 2000;32:783-7.
3. Mann K, Rendl J, Busley R, et al. Systemic iodine absorption during endoscopic application of radiographic contrast agents for endoscopic
retrograde cholangiopancreaticography. Eur J Endocrinol 1994;130:
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4. Monig H, Arendt T, Eggers S, et al. Iodine absorption in patients undergoing ERCP compared with coronary angiography. Gastrointest
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5. Fassbender WJ, Vogel C, Doppl W, et al. Thyroid function, thyroid
immunoglobulin status, and urinary iodine excretion after enteral
contrast-agent administration by endoscopic retrograde cholangiopancreatography. Endoscopy 2001;33:245-52.
6. Morcos SK, Thomsen HS. Adverse reactions to iodinated contrast media. Eur Radiol 2001;11:1267-75.
7. Valls C, Andia E, Sanchez A, et al. Selective use of low-osmolality
contrast media in computed tomography. Eur Radiol 2003;13:2000-5.
8. Katayama H, Yamaguchi K, Kozuka T, et al. Adverse reaction to ionic
and nonionic contrast media. Report from the Japanese Committee
on the Safety of Contrast Media. Radiology 1990;75:621-8.
9. Draganov P, Cotton PB. Iodinated contrast sensitivity in ERCP. Am J
Gastroenterol 2000;95:1398-401.
10. Lasser EC, Berry CC, Talner LB, et al. Pretreatment with corticosteroids
to alleviate reactions to intravenous contrast material. N Engl J Med
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11. Lasser EC, Berry CC, Mishkin MM, et al. Pretreatment with corticosteroids to prevent adverse reactions to nonionic contrast media. AJR
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13. American College of Radiology Committee on Drugs and Contrast
Media. Manual on contrast media, 5.0 edition. Reston (VA): ACR;
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14. Mosca S, Secondulfo M, Defez M, et al. Air contrastography technique
for successful urgent ERCP in a high risk allergic patient. Am J Gastroenterol 2001;96:3458-60.
15. Poneros JM, Tearney GJ, Shiskov M, et al. Optical coherence tomography of the biliary tree during ERCP. Gastrointest Endosc 2002;55:
84-8.
16. Freeman ML, DiSario JA, Nelson DB, et al. Risk factors for post-ERCP
pancreatitis: a prospective, multicenter study. Gastrointest Endosc
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17. Petersen BT. ERCP outcomes: defining the operators, experience, and
environments. Gastrointest Endosc 2002;55:953-8.
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18. Pezzilli R, Romboli E, Campana D, et al. Mechanisms involved in the
onset of post-ERCP pancreatitis. JOP 2002;3:162-8.
19. George S, Kulkarni AA, Stevens G, et al. Role of osmolality of contrast
media in the development of post-ERCP pancreatitis: a metanalysis.
Dig Dis Sci 2004;49:503-8.
20. Jendrzejewski JW, McAnally T, Jones SR, et al. Antibiotics and ERCP: in
vitro activity of aminoglycosides when added to iodinated contrast
agents. Gastroenterology 1980;78:745-8.
21. Collen MJ, Hanan MR, Maher JA, et al. Modification of endoscopic retrograde cholangiopancreatography (ERCP) septic complications by
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22. Pugliese V, Saccomanno S, Bonelli L, et al. Is it useful to add gentamycin to contrast media in endoscopic retrograde cholangiopancreatography? Prospective evaluation of 330 cases [in Italian]. Minerva Dietol
Gastroenterol 1986;32:149-56.
23. Siegel JH, Korsten MA, Gottfried E, et al. Antibiotics and ERCP. Gastroenterology 1980;79:605-6.
484 GASTROINTESTINAL ENDOSCOPY Volume 62, No. 4 : 2005
Prepared by:
TECHNOLOGY ASSESSMENT COMMITTEE
Daniel Mishkin, MD
Steven Carpenter, MD
Joseph Croffie, MD
Ram Chuttani, MD
James DiSario, MD
Nadeem Hussain, MD
Julia Liu, MD
Lehel Somogyi, MD
William Tierney, MD
Bret T. Petersen, MD, Chair
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